The compounds of the present invention can be used in the treatment of disorders resulting from problems of which the cause lies in the central serotonergic system and which are known to be mediated in the reuptake of serotonin and/or at the level of 5-HT1A receptors, such as anxiety, panic attacks, obsessive-compulsive disorders, impulsive disorders, cognitive disorders, phobias and depression.
Regarding the treatment of depression, selective serotonin reuptake inhibitors (SSRI) currently represent one of the most effective classes of medicaments. Their beneficial therapeutic effects, however, do not become apparent before the end of the second week of treatment at the minimum, and most of the time do not become apparent until during the third or even the fourth week. This major drawback is damaging to the efficacy of that class of products. The latent period can be explained by the desensitisation of the 5-HT1A receptors of the cell bodies. Indeed it has been demonstrated (TIPS, 1993, 14, 262) that the efficacy of an SSRI such as fluoxetine may be reduced by the activation of 5-HT1A receptors, that activation resulting in a reduction in the discharge frequency of serotonergic neurons.
Consequently, a blockade of 5-HT1A receptors could lead to a more effective treatment (by reducing the latent period). Recently, a clinical study carried out with a partial 5-HT1A agonist Clin. Psychopharmacol., 1995, 15, 217) demonstrated that such a substance may improve the efficacy of a concomitantly administered SSRI and/or may result in a reduction in the time taken for a concomitantly administered SSRI to take effect.
In vitro and in vivo experiments have made it possible to demonstrate that the compounds of the present invention combine a selective inhibitory-type activity in respect of the reuptake of serotonin (SSRI) with a partial agonist or antagonist activity in respect of 5-HT1A receptors. Thus, owing to their specific pharmacological activity, in addition to the fact that the compounds of the present invention are new, they may be useful in the treatment of anxiety, depression, panic attacks, obsessive-compulsive disorders, phobias, impulsive disorders and cognitive disorders.
Compounds of similar structures have already been described in the literature. This applies especially to the Patent Applications FR 2 738 822 and FR 2 738 823, which claim, in particular, compounds having a 4-(1-piperazinyl)thieno[3,2-c]pyridine moiety. Those compounds are useful in the treatment of hypertension, cardiac insufficiency, arthritis and microcirculation disorders. The Patent US 4 677 104 claims compounds having either a 4-(1-piperazinyl)thieno, or furo, or 1H-pyrrolo[3,2-c]pyridine moiety, or a 7-(1-piperazinyl)thieno, or furo, or 1H-pyrrolo[2,3-c]pyridine moiety, those compounds being usefull as antipsychotic or anxiolytic agents. Those compounds are substantially distinguished from the compounds described in the present invention by the presence of a very different ring system substituted on the piperazinyl moiety.
The present invention relates more especially to compounds of formula (I): 
wherein:
W represents:
either a naphthyl group optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6)alkoxy, cyano, nitro, linear or branched trihalo(C1-C6)alkyl, methylenedioxy and ethylenedioxy,
or a group of formula Y where: 
wherein E, together with the carbon atoms of the phenyl ring to which it is bonded, represents an unsaturated, partially saturated, or aromatic, monocyclic ring having from 5 to 7 ring members and containing at least one hetero atom selected from oxygen, nitrogen and sulphur, it being possible for the said group Y to be bonded to the (CH2)n group of the compounds of formula (I) either by the phenyl moiety or by the monocyclic ring E, and for each of the said Y groups to be optionally substituted by one or more identical or different groups selected from halogen, hydroxy, cyano, nitro, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, linear or branched trihalo(C1-C6)alkyl, heterocycloalkylalkylene in which the alkylene moiety contains from 1 to 6 carbon atoms and may be linear or branched (and in which the heterocyclic ring is an unsaturated or aromatic monocyclic ring having 5 or 6 ring members and containing from 1 to 4 hetero atoms selected from nitrogen, sulphur and oxygen) and oxo,
provided that in that case the group Y can be substituted only by a single oxo group and that E, together with the carbon atoms of the phenyl ring to which it is bonded, represents then a monocyclic ring having 5 ring members and containing two identical or different hetero atoms selected from oxygen and nitrogen,
n represents an integer from 1 to 6 inclusive,
Z represents a single bond, an oxygen atom, or a nitrogen atom substituted by a group selected from hydrogen, linear or branched (C1-C6)alkyl (itself optionally substituted by one or more hydroxy groups) and aryl-(C1-C6)alkyl in which the alkyl moiety may be linear or branched,
A represents a CH group or a nitrogen atom,
Q represents a CH group or a nitrogen atom, provided that at least one of the groups A and Q represents a nitrogen atom, and that A represents a nitrogen atom when Z represents a single bond, and
M, together with the carbon atoms of the phenyl ring to which it is bonded, represents a thieno, furo, pyrrolo or oxopyrrolo group,
to their isomers, and to addition salts thereof with a pharmaceutically acceptable acid or base.
xe2x80x9cArylxe2x80x9d is to be understood as meaning a phenyl, naphthyl, dihydronaphthyl or tetrahydronaphthyl group.
Advantageouly, preferred W substituents of the invention are the groups naphthyl, 2,3-dihydro-1,4-benzodioxinyl, chromanyl, 2H-chromenyl, isochromanyl, 2,3-dihydrobenzofuranyl, benzofuranyl, 1,3-dihydro-2H-benzimidazol-2-one, 1,3-benzoxazol-2-one and indolyl.
Where W is optionally substituted by a heterocycloalkylalkylene group in which the alkylene moiety is linear or branched and contains from 1 to 6 carbon atoms, the said heterocycloalkylalkylene group is advantageously a heterocycloalkylmethylene group in which heterocycloalkyl is an unsaturated or aromatic monocyclic ring having 5 ring members and containing from 1 to 4 nitrogen atoms. Preferably, the said heterocycloalkyl-methylene group is a 1,2,4-triazol-1-ylmethyl, imidazol-1-ylmethyl or 1H-imidazol-5-ylmethyl group.
In an especially advantageous embodiment, the substituents W preferred in accordance with the invention are the groups 1-naphthyl, isochroman-1-yl and 2,3-dihydro-1-benzofuran-5-yl.
In another especially advantageous embodiment, the substituents W preferred in accordance with the invention are the 5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl group, the 5-(imidazol-1-ylmethyl)-1H-indol-3-yl group and the 5-(1H-imidazol-5-ylmethyl)-1H-indol-3-yl group.
In a third especially advantageous embodiment, the substituents W preferred in accordance with the invention are the groups 1,3-benzoxazol-2-on-1-yl and 1,3-dihydro-2H-benzimidazol-2-on-1-yl.
Preferably, Z represents a single bond in the compounds of the invention.
According to a valuable embodiment, preferred compounds of the invention are compounds of formula (I) wherein Z represents a nitrogen atom substituted by a group selected from hydrogen, methyl and hydroxyethylene when A represents a CH group, Q represents a nitrogen atom, n is 1 and W represents a 2-naphthyl group.
According to an advantageous embodiment of the invention, preferred compounds are those wherein n represents 2 or 3.
According to another advantageous embodiment of the invention, preferred compounds are those wherein M, together with the carbon atoms of the phenyl ring to which it is bonded, represents a thienyl or furyl group.
Preferred compounds of the invention are especially advantageously:
4-{1-[2-(1-naphthyl)ethyl]-4-piperidinyl}thieno[3,2-c]pyridine,
4-{1-[2-(1-naphthyl)ethyl]-4-piperidinyl}furo[3,2-c]pyridine,
4-{4-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-1-piperazinyl}furo[3,2-c]pyridine,
4-{4-[2-(isochroman-1-yl)ethyl]-1-piperazinyl}thieno[3,2-c]pyridine,
4-(4-{2-[5-1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethyl}-1-piperazinyl)-furo[3,2-c]pyridine,
4-(4-{2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethyl}-1-piperazinyl)-1H-pyrrolo[3,2-c]pyridine,
1-[2-(4-furo[3,2-c]pyridin-4-yl-1-piperazinyl)ethyl]-1,3-dihydro-2H-benzimidazol-2-one,
and 1-[2-(4thieno[3,2-c]pyridin-4-yl-1-piperazinyl)ethyl]-1,3-dihydro-2H-benzimidazol-2-one.
The isomers, and also the addition salts with a pharnaceutically acceptable acid or base, of the preferred compounds form an integral part of the invention.
Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid, etc.
Among the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
The invention extends also to a process for the preparation of the compounds of formula (I), which is characterised in that there is used as starting material a compound of formula (II): 
wherein M is as defined for formula (I) and X represents a chlorine, bromine or iodine atom or a leaving group, such as mesyl, tosyl or triflyl,
which compound of formula (II) is reacted in the presence of a base with a compound of formula (III): 
wherein W, n and A are as defined for formula (I), Q1 represents a nitrogen atom and Z1 represents a single bond, an oxygen atom or an NH group,
to yield the compounds of formula (I/a), a particular case of the compounds of formula (I): 
wherein W, n, Z1, A, M and Q1 are as defined hereinbefore,
or which compounds of formula (II) are converted, in accordance with the conventional conditions of organic synthesis, into compounds of formula (IV): 
wherein A, Q and M are as defined for formula (I), and Z2 represents a hydrogen atom when A represents a nitrogen atom or Z2 represents an NH2 group when A represents a CH group,
which compounds of formula (IV) are reacted,
either with a compound of formula (V)
Wxe2x80x94(CH2)nxe2x88x921xe2x80x94CO2Hxe2x80x83xe2x80x83(V)
xe2x80x83wherein W and n are as defined for formula (I), in the presence of a coupling agent, to yield the compounds of formula (VI): 
wherein W, n, A, Q and M are as defined for formula (I), and Z3 represents a bond when A represents a nitrogen atom or Z3 represents an NH group when A represents a CH group,
which compounds of formula (VI) are treated with a reducing agent, in accordance with conventional conditions of organic synthesis, to yield the compounds of formula (I/b), a particular case of the compounds of formula (I): 
wherein W, n, A, Q, M and Z3 are as defined hereinbefore,
or with a compound of formula (VII):
Wxe2x80x94(CH2)nxe2x88x921xe2x80x94CHOxe2x80x83xe2x80x83(VII)
wherein W and n are as defined hereinbefore, under reductive amination conditions, to yield, directly, the compounds of formula (I/b) as defined hereinbefore,
or with a compound of formula (VIII):
Wxe2x80x94(CH2)nxe2x80x94Xxe2x80x83xe2x80x83(VIII)
wherein W and n are as defined hereinbefore and X represents a chlorine, bromine or iodine atom or a leaving group, such as tosyl, mesyl or triflyl, in the presence of a phase transfer agent or a base,
also to yield, directly, the compounds of formula (I/b) as defined hereinbefore, the compounds of formulae (I/a) and (I/b) constituting the compounds of formula (I/c): 
wherein W, n, A, Q and M are as defined for formula (I) and Z4 represents a bond, an oxygen atom or an NH group,
which compounds of formula (I/c), when Z4 is Zxe2x80x24 and represents an NH group, and A is A1 and represents a CH group, are subjected to an alkylation reaction according to conventional methods of organic synthesis to yield the compounds of formula (I/d), a particular case of the compounds of formula (I): 
wherein W, n, Q, M and A1 are as defined hereinbefore and Z5 represents a nitrogen atom substituted by a linear or branched (C1-C6)alkyl group (itself optionally substituted by one or more hydroxy groups) or by aryl-(C1-C6)alkyl in which the alkyl moiety may be linear or branched,
the compounds (I/a) to (I/d) constituting the totality of the compounds of the invention, which compounds are purified, if necessary, according to conventional purification techniques, are separated, if desired, into their isomers according to a conventional separation technique, and are converted, if desired, into addition salts with a pharmaceutically acceptable acid or base.
The compounds of formulae (II), (III), (V), (VII) and (VIII) are either commercially available compounds or compounds obtained according to conventional methods of organic synthesis.
The present invention extends also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), an isomer thereof or an addition salt thereof with a pharmaceutically acceptable acid or base, alone or in combination with one or more pharmaceutically acceptable, inert, non-toxic excipients or carriers.
Among the pharmaceutical compositions according to the invention there may be mentioned more especially those which are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous) per- or trans-cutaneous, nasal, rectal, perlingual, ocular or respiratory administration, and especially tablets or dragxc3xa9es, sublingual tablets, soft gelatin capsules, hard gelatin capsules, suppositories, creams, ointments, dermal gels, injectable or drinkable preparations, aerosols, eye or nose drops, etc.
In view of the selective inhibitory activity in respect of serotonin reuptake and the 5-HT1A receptor partial agonist or antagonist activity of the compounds of the invention, the pharmaceutical compositions comprising as active ingredient at least one compound of the invention are useful in the treatment of depression, anxiety, panic attacks, obsessive-compulsive disorders, phobias, impulsive disorders and cognitive disorders.
The useful dosage varies in accordance with the the age and weight of the patient, the route of administration, the nature and severity of the disorder and the administration of possible associated treatements and ranges from 0.5 to 50 mg in one or more administrations per day.